EXTH-45. PRECLINICAL EVALUATION OF THE ANTIBODY-DRUG CONJUGATE TISOTUMAB VEDOTIN IN ADULT-TYPE DIFFUSE GLIOMAS

Abstract The gene F3, encoding Tissue Factor (TF), is expressed in many cancers and contributes to their malignancy. Our previous work showed that, among adult-type diffuse gliomas, IDH wild-type (IDHwt) glioblastomas (GBM) express more TF than IDH mutant (IDHmut) gliomas (PMID: 27664011, 30266764, 31222125). Tisotumab vedotin (TV), an anti-TF antibody conjugated to monomethyl auristatin E, is a therapeutic designed to target cells expressing TF. We therefore sought to determine the therapeutic potential of TV in IDHwt vs. IDHmut gliomas. TV was more active against cultured IDHwt GBM cells than IDHmut glioma cells (P<0.0001). This activity was increased by 55% with daily washout of the soluble TF secreted by IDHwt GBM cells. TV extended the survival of mice intracranially engrafted with IDHwt GBM by 34% (37.5 days vs. 28 days for IgG control, P=0.006), but not mice with IDHmut glioma (30.5 days, P=0.88). TV also reduced the growth of IDHwt GBM flank xenografts by 58% (P=0.045). Unconjugated tisotumab had no antitumor effect intracranially or in the flank. All 12 flank-engrafted mice treated with tisotumab, and 9/12 mice treated with TV, developed large hematomas in and around the flank xenografts, compared to 0/12 IgG-treated mice (P<0.001). Similarly, a semiquantitative analysis showed that intracerebral hemorrhage was more extensive in tisotumab/TV- treated GBM12 mice than in IgG-treated GBM12 mice (P=0.046). These data indicate that TV targets high TF-expressing IDHwt GBM, but not low TF-expressing IDHmut glioma, that its activity is predominately through the vedotin conjugate rather than inhibition of TF signaling, and that it may have some effect against TF-expressing IDHwt GBM, but intracerebral hemorrhage may be a concern.